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CCN2 regulates smooth muscle cell trans-differentiation and lipid accumulation in atherosclerosis

ABSTRACT: Accruing evidence illustrates an emerging paradigm of dynamic vascular smooth muscle cell (SMC) trans-differentiation during atherosclerosis progression. However, the molecular regulators that govern SMC phenotype diversification remain poorly defined. This study aims to elucidate the functional role and underlying mechanisms of cellular communication network factor 2 (CCN2), a matricellular protein, in regulating SMC plasticity in the context of atherosclerosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE278184 | GEO | 2025/01/08

REPOSITORIES: GEO

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CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development

Project description:Vascular smooth muscle cell (VSMC) phenotypic switching is widely recognized as a key mechanism responsible for the pathogenesis of several aortic diseases such as aortic aneurysm. Cellular communication network factor 2 (CCN2), often upregulated in human pathologies and animal disease models, exerts a myriad of context-dependent biological functions. However, current understanding of the role of SMC-CCN2 in SMC phenotypic switching and its function in the pathology of abdominal aortic aneurysm (AAA) is lacking. Here we report the effect of SMC-restricted CCN2 deficiency of hypercholesterolemic mice on gene expression in infrarenal aorta with or without angiotensin II (Ang II)-infusion.

2023-03-02 | GSE221399 | GEO

Transcriptomic changes associated with CCN2/CTGF deficiency in the mouse embryonic retina

Project description:The cellular communication network (CCN) 2, also known as CTGF, is a secreted matricellular protein with regulatory functions in vasoproliferative and fibrotic diseases. Although CCN2 functions extend to developmental processes, the impact of CCN2/CTGF expression, or lack thereof, during retinogenesis is unknown. Herein, we used bulk RNA-sequencing to determine the transcriptomic changes associated with global deletion of CCN2 in E18.5 mouse retinas. we show that CCN2 signals act on intrinsic signal transduction pathway genes and induce genetic reprogramming of retinal progenitor cells endowing these cells with neurogenic and gliogenic potentials.

2022-04-01 | GSE171232 | GEO

Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human [mouse]

Project description:Smooth muscle cells (SMC) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration and transdifferentiation into other cell types. Yet, how SMC contribute to pathophysiology of atherosclerosis remains elusive. To reveal the trajectories of SMC transdifferentiation during atherosclerosis and to identify molecular targets for disease therapy, we combined SMC fate mapping and single-cell RNA sequencing of both mouse and human atherosclerotic plaques.

2020-10-06 | GSE155513 | GEO

Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human [human]

2020-10-06 | GSE155512 | GEO

Macrophage extracellular traps originated from the vascular smooth muscle cells play key roles in atherosclerosis progression [scRNA-seq]

Project description:Smooth muscle cells (SMC) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC transdifferentiation into macrophage-like SMCs. Furthermore, during transdifferentiation, the SMCs' expression of PADI4 upregulating and SMC generated extracellular trap, a web-like structure, which plays key role in the development of atherosclerosis plaque. To reveal the function of SMC's generating ETs during atherosclerosis and to identify molecular targets for disease therapy, we combined SMC fate mapping and single-cell RNA sequencing of mouse atherosclerotic plaques.

2022-11-04 | GSE197073 | GEO

Macrophage extracellular traps originated from the vascular smooth muscle cells play key roles in atherosclerosis progression [RNA-seq]

Project description:Smooth muscle cells (SMC) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC transdifferentiation into macrophage-like SMCs. Furthermore, during transdifferentiation, the SMCs' expression of PADI4 upregulating and SMC generated extracellular trap, a web-like structure, which plays key role in the development of atherosclerosis plaque. To reveal the potential mechanism of the SMC derived macrophages generated ETs surducing surrounding SMCs within the media of artery during the process of atherosclerosis plaque development, we utilized the dsDNA and H3CIT protein to stimuli the SMCs, the SMC stimulated with 0.2%BSA as coontrol group, we collect the cells and did RNA-sequencing between two groups to find the potential signaling pathway participating in the process

2022-11-04 | GSE197074 | GEO

Smooth muscle cell-specific translatome profiling of mouse atherosclerosis uncovers Itih4 as a novel SMC-enriched gene

Project description:The development of atherosclerosis, a chronic disease characterized by the buildup of plaque in arterial walls, involves the contribution of vascular smooth muscle cells (SMCs) and SMC-derived cells. To better understand the specific role of SMCs in atherosclerosis, a transgenic mouse line expressing EGFP-tagged ribosomal protein L10a (EGFP-L10a) under the SMC-specific αSMA promoter (SMCTRAP mice) was developed, enabling translating ribosome affinity purification followed by sequencing (TRAP-Seq). SMCTRAP mice were crossed with an atherosclerosis model (SMCTRAP-Athero mice). Using TRAP-Seq and bulk RNA-Seq, the aortas of 15-month-old SMCTRAP and SMCTRAP-Athero mice were analyzed to identify atherosclerosis-induced changes in the profiles of SMC ribosome-associated RNA. The results showed high enrichment of known SMC-specific genes in the TRAP fraction, indicating the specificity of the construct. The intersection of SMC-specific genes identified by TRAP-Seq, and atherosclerosis-induced genes identified by bulk RNA-Seq revealed the contribution of SMCs to the expression of several known disease-induced genes, as well as the identification of previously unlinked genes in atherosclerosis that warrant further investigation. These findings provide new insights into the role of SMCs in atherosclerosis and may offer potential targets for future treatments of this chronic disease.

2024-02-08 | GSE225424 | GEO

CCN2-MAPK-Id-1 Loop Feedback Amplification is involved in Maintaining Stemness in Oxaliplatin-resistant Hepatocellular Carcinoma

Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Most patients are at an advanced stage at diagnosis, and are not eligible for curative therapy. Chemotherapy is an alternative treatment for advanced HCCs, but resistance is found in many patients. Understanding the underlying mechanisms in chemo-resistance is critical to further improve the efficacy of HCC treatment. In this study, we found that increased expression of Id-1 and CCN2 were closely related to oxaliplatin resistance in HCC. Upregulation of CCN2 and Id-1 was independently associated with shorter survival and increased recurrence in HCC patients, and significantly enhanced oxaliplatin resistance and promoted lung metastasis in vivo, whereas knock-down of their expression significantly reversed the chemo-resistance and inhibited HCC cell stemness. cDNA microarrays and PCR revealed that Id-1 and MAPK pathway were the downstream signaling of CCN2, and Id-1 could upregulate CCN2 in a positive feedback manner. Moreover, CCN2 significantly enhanced oxaliplatin resistance by activating the MAPK signaling pathway and upregulating Id-1 expression. Meanwhile, MAPK/Id-1 signaling was demonstrated as one of the most important autocrine signaling pathways regulated by CCN2 in oxaliplatin-resistant models, and combination with sorafenib could improve the efficacy of oxaliplatin in HCC. Conclusions: These findings suggest that CCN2-MAPK-Id-1 loop feedback amplification is involved in oxaliplatin-resistant HCC, and the combination of oxaliplatin with inhibitor of CCN2 or MAPK signaling could provide a promising approach to ameliorating HCC progression and oxaliplatin resistance.

2019-01-02 | GSE124529 | GEO

Comparative proteomics reveal elevated CCN2 in NGLY1 deficient cells

Project description:N-glycanase 1(NGLY1) catalyzes the removal of N-linked glycans from newly synthesized or misfolded protein to exert protein quality control function via the process of endoplasmic reticulum-associated degradation (ERAD). NGLY1 deficiency (OMIM 615273) is a newly diagnosed rare genetic disorder with ~60 patients worldwide to date. The affected individuals present a broad spectrum of clinical features, including developmental delay, seizures, muscle weakness, liver failure, and the reduced secretion of sweats and tears. Recent studies explored several possible molecular mechanisms of NGLY1 deficiency including in vivo proteostasis, mitochondrial homeostasis, innate immunity, water and ion transport, with the goal of linking these findings to the pathophysiology of the disease. This study focuses on the dysregulation of ERAD in NGLY1 deficiency. We demonstrate the abnormal accumulation of ERAD substrates in NGLY1 deficient cells. Comprehensive global quantitative proteomics discovered elevated levels of novel endogenous proteins in NGLY1 defective human and mouse cells. Further biological validation assays confirmed the altered abundance of several key candidates’ that were observed in the isobarically labeled proteomic experiments. CCN2 was selected for further analysis due to its high fold change in different cell models of NGLY1 deficiency. Functional assays show elevated CCN2 and over-stimulated TGF-β signaling in NGLY1 deficient cells. Given the important role of CCN2 and TGF-β pathway in mediating systemic fibrosis, we propose a potential link of increased CCN2 and TGF-β signaling to microscopic liver fibrosis in NGLY1 patients.

2021-12-21 | PXD026301 | Pride

Analysis of Wild Type and miR-21-/- Smooth Muscle Cell Transcriptomes after atherosclerosis

Project description:Purpose: The goals of this study are to investigate the effect of miR-21 knockout in aortic smooth muscle cell transcriptome profiling (RNA-seq) to understand how miR-21 regulates SMC plasticity during atherosclerosis. Methods: Aortic smooth muscle cell (SMC) mRNA profiles of 30-week-old wild-type (WT) and SMC specific miR-21 knockout (miR-21fl/flmTmG/Myh11ERT2) mice fed on western diet for 20 weeks were generated by deep sequencing, in triplicate. The sequence reads that passed quality filters were analyzed at the transcript isoform level . qRT–PCR validation was performed using TaqMan and SYBR Green assays to confirm miR-21 knockout. Results: Using an optimized data analysis workflow, we mapped about 60 million sequence reads per sample to the mouse genome (build mm10) and identified 22,836 transcripts in the SMCs of WT and miR-21fl/flmTmG/Myh11ERT2 mice. RNA-seq data revealed ~300 genes differentially expressed in miR-21 knockout SMCs after atherosclerosis. Hierarchical clustering of differentially expressed genes uncovered several as yet uncharacterized pathways that may contribute to SMC function during atherosclerosis progression. Conclusions: Our study represents the first detailed analysis of SMC lacking of miR-21 transcriptomes, with biologic replicates, generated by RNA-seq technology. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles. Our results show that NGS offers a comprehensive and more accurate quantitative and qualitative evaluation of mRNA content within a cell or tissue. We conclude that RNA-seq based transcriptome characterization would expedite genetic network analyses and permit the dissection of complex biologic functions.

2022-06-10 | GSE183829 | GEO

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